immunology research journal articles

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Research articles

Affinity gaps among B cells in germinal centers drive the selection of MPER precursors

Batista, Schief and colleagues use a series of germline-targeting immunogens in knock-in mice expressing heavy chain sequences derived from the HIV broadly neutralizing antibody 10E8 to characterize the requirements of 10E8 B cell precursors for entry and maturation in the germinal center.

• Torben Schiffner
• Facundo D. Batista

Vaccination induces broadly neutralizing antibody precursors to HIV gp41

Schief and colleagues show that germline-targeting epitope scaffolds can elicit responses from rare broadly neutralizing antibody precursor B cells with predefined binding specificities and genetic features.

• William R. Schief

Alternative platelet differentiation pathways initiated by nonhierarchically related hematopoietic stem cells

Jacobsen and colleagues elucidate the nonhierarchical relationship between two types of stem cells: Vwf − hematopoietic stem cells that stably replenish all blood cell lineages without a platelet bias, and Vwf + stem cells that replenish almost exclusively platelets, and demonstrate that the two types utilize cellularly and molecularly distinct progenitor trajectories for replenishment of platelets.

• Joana Carrelha
• Stefania Mazzi
• Sten Eirik W. Jacobsen

Antitumor progenitor exhausted CD8 + T cells are sustained by TCR engagement

Chronic antigen exposure promotes terminal exhaustion of T cells. Here the authors show a role for TCR stimulation in preserving progenitor exhausted T cells and highlight their TCR-dependent self-renewal during antitumor responses.

• Ben Youngblood

An IFNγ-dependent immune–endocrine circuit lowers blood glucose to potentiate the innate antiviral immune response

Sestan et al. find a conserved mechanism during systemic viral infection in which γδ T cells produce IFNγ to increase pancreatic insulin secretion, lowering blood glucose and then enhancing type I interferon-mediated protection against viral infection.

• Marko Šestan
• Sanja Mikašinović
• Bojan Polić

Cytokine polarized, alternatively activated bone marrow neutrophils drive axon regeneration

Segal and colleagues identify a population of immature neutrophils as having regenerative properties on injured neurons and being capable of inducing axon regeneration. These findings suggest potential strategies for restoring lost neurological functions in central nervous system disorders.

• Andrew D. Jerome
• Andrew R. Sas
• Benjamin M. Segal

Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade

Immunosuppression is regulated by the circadian clock and can be leveraged to promote the efficacy of immune checkpoint inhibitor therapy.

• Bridget M. Fortin
• Shannon M. Pfeiffer
• Selma Masri

Nociceptor-immune interactomes reveal insult-specific immune signatures of pain

Woolf and colleagues use single-cell transcriptomics to determine the gene signature of infiltrating immune cells and potential cell–cell interactions between receptors, ligands, ion channels and metabolites expressed on immune cells and sensory neurons in three models of pain.

• Aakanksha Jain
• Benjamin M. Gyori
• Clifford J. Woolf

Perinatal thymic-derived CD8αβ-expressing γδ T cells are innate IFN-γ producers that expand in IL-7R–STAT5B-driven neoplasms

Here the authors identify and characterize the development and function of an IFN-γ-producing CD8αβ + subset of γδ T cells that contributes to malignancy.

• Nital Sumaria
• Gina J. Fiala
• Bruno Silva-Santos

A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice

CAR T cells have shown great promise in treating some cancers and are now being applied to other diseases. Here the authors engineer mouse and human T cells and show that a single infusion can result in lasting remission from asthma in mice.

The aged tumor microenvironment limits T cell control of cancer

Cancer and aging are associated with each other, but underlying mechanisms contributing to this correlation are unclear. Here the authors identify a dysfunctional T cell state that is distinct from typical T cell exhaustion and only occurs in the tumor microenvironment during later life.

• Alex C. Y. Chen
• Sneha Jaiswal
• Debattama R. Sen

Predictability of B cell clonal persistence and immunosurveillance in breast cancer

In this Resource paper, the authors integrate T cell antigen receptor, B cell antigen receptor and exome sequencing comparing early and metastatic breast cancer in humans, showing how the immune response and tumors coevolve.

• Stephen-John Sammut
• Jacob D. Galson
• Rachael J. M. Bashford-Rogers

Coordinated chemokine expression defines macrophage subsets across tissues

Jakubzick and colleagues show that interstitial macrophages across various tissues display similar coordinated chemokine signatures in humans and mice.

• Arlind B. Mara
• Claudia V. Jakubzick

Temporal dynamics and genomic programming of plasma cell fates

Singh and colleagues show Tigit controls the generation of germinal center-derived plasma cell precursors that give rise to long-lived differentiated progeny in the bone marrow.

• Godhev Kumar Manakkat Vijay
• Harinder Singh

Sepsis-trained macrophages promote antitumoral tissue-resident T cells

Here the authors show that sepsis and its resolution alter cancer susceptibility by epigenetically altering resident macrophages resulting in retention of T cells that increase antitumoral immunity.

• Alexis Broquet
• Victor Gourain
• Antoine Roquilly

Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary β-glucan-induced inflammatory adaptation

In this study, the authors suggest that in the lung ApoE is a checkpoint for monocyte-to-macrophage differentiation triggered by the dectin1–Card9 pathway.

• H. Theobald
• D. A. Bejarano
• A. Schlitzer

A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron

Here the authors show that a heteropolysaccharide from a commensal bacteria commonly found in the Korean food kimchi is able to bolster antitumor immune responses by instructing tumor-associated macrophages to release lipocalin-2, which sequesters iron away from tumor cells contributing to the immune response to attack these cells.

• Garima Sharma
• Amit Sharma
• Sin-Hyeog Im

JAK-STAT signaling maintains homeostasis in T cells and macrophages

Bock and colleagues perform integrative analysis of JAK-STAT mutant mice and find JAK-STAT signaling regulates CD8 + T cell and macrophage homeostasis by contributing to a poised epigenetic and transcription-regulatory state, preparing cells to rapidly respond to stimuli.

• Nikolaus Fortelny
• Matthias Farlik
• Christoph Bock

Hepatocytes coordinate immune evasion in cancer via release of serum amyloid A proteins

Here the authors show how the liver affects the immune response to pancreatic ductal adenocarcinoma and that cancer immunity and survival outcomes after surgery might be bolstered by therapeutic intervention on hepatocyte release of serum amyloid A proteins.

• Meredith L. Stone
• Gregory L. Beatty

PU.1 and BCL11B sequentially cooperate with RUNX1 to anchor mSWI/SNF to poise the T cell effector landscape

Koh et al. show that loci active in differentiated effector T cells are poised in early T precursors before the expression of T cell antigen receptors in a manner dependent on the chromatin remodeling complex mammalian SWItch/Sucrose Non-Fermentable and the PU.1–RUNX1 and BCL11B–RUNX1 complexes.

• Noah Gamble
• Alexandra Bradu
• Andrew S. Koh

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Immune mechanisms in food allergy

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Identification of four mitochondria-related genes in sepsis based on RNA sequencing technology

Authors: ShilinLi and Yingchun Hu

Potential role of IGF-1R in the interaction between orbital fibroblasts and B lymphocytes: an implication for B lymphocyte depletion in the active inflammatory phase of thyroid-associated ophthalmopathy

Authors: Renyan Wang, Delu Song, Yong Zhong and Hui Li

Atypical skin conditions of the neck and back as a dermal manifestation of anti-HMGCR antibody-positive myopathy

Authors: Takashi Kurashige, Rie Nakamura, Tomomi Murao, Naoko Mine, Mayu Sato, Riho Katsumata, Yuhei Kanaya, Yoriko Dodo, Tomohito Sugiura and Tomohiko Ohshita

GNUV201, a novel human/mouse cross-reactive and low pH-selective anti-PD-1 monoclonal antibody for cancer immunotherapy

Authors: Hae-Mi Kim, Kyoung-Jin Kim, Kwanghyun Lee, Myeong Jin Yoon, Jenny Choih, Tae-Joon Hong, Eun Ji Cho, Hak-Jun Jung, Jayoung Kim, Ji Soo Park, Hye Young Na, Yong-Seok Heo, Chae Gyu Park, Heungrok Park, Sungho Han and Donggoo Bae

Effect of immune-modulating metronomic capecitabine as an adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma

Authors: Qianyong He, Xiuling Luo, Lina Liu, Chaofen Zhao, Zhuoling Li and Feng Jin

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Revisiting the white blood cell count: immature granulocytes count as a diagnostic marker to discriminate between SIRS and sepsis - a prospective, observational study

Authors: Axel Nierhaus, Stefanie Klatte, Jo Linssen, Nina M Eismann, Dominic Wichmann, Jörg Hedke, Stephan A Braune and Stefan Kluge

Characterization of murine macrophages from bone marrow, spleen and peritoneum

Authors: Changqi Wang, Xiao Yu, Qi Cao, Ya Wang, Guoping Zheng, Thian Kui Tan, Hong Zhao, Ye Zhao, Yiping Wang and David CH Harris

Transcriptional profiling of the LPS induced NF-κB response in macrophages

Authors: Omar Sharif, Viacheslav N Bolshakov, Stephanie Raines, Peter Newham and Neil D Perkins

Prerequisites for cytokine measurements in clinical trials with multiplex immunoassays

Authors: Wilco de Jager, Katarzyna Bourcier, Ger T Rijkers, Berent J Prakken and Vicki Seyfert-Margolis

HLA class I supertypes: a revised and updated classification

Authors: John Sidney, Bjoern Peters, Nicole Frahm, Christian Brander and Alessandro Sette

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Helminth-derived proteins as immune system regulators: a systematic review of their promise in alleviating colitis.

Through a systematic review, Alghanmi and colleagues highlight the role of helminth-derived proteins in immunomodulation and their potential utility in treatment for chronic inflammatory conditions such Crohn’s disease.

Whole blood stimulation provides preliminary evidence of altered immune function following SRC

Battista and colleagues explore how whole blood stimulation can be used within a causal framework to estimate the effect of sports-related concussion (SRC) on immune function. Preliminary evidence suggests that SRC affects LPS and R848 immunoreactivity.

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An introduction to immunology and immunopathology

Jean s. marshall.

1 Department of Microbiology and Immunology, Dalhousie University, Halifax, NS Canada

Richard Warrington

2 Section of Allergy & Clinical Immunology, Department of Internal Medicine, University of Manitoba, Winnipeg, MB Canada

Wade Watson

3 Division of Allergy, Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, NS Canada

Harold L. Kim

4 Western University, London, ON Canada

5 McMaster University, Hamilton, ON Canada

Associated Data

Data sharing not applicable to this article as no datasets were generated or analyzed during the development of this review.

Beyond structural and chemical barriers to pathogens, the immune system has two fundamental lines of defense: innate immunity and adaptive immunity. Innate immunity is the first immunological mechanism for fighting against an intruding pathogen. It is a rapid immune response, initiated within minutes or hours after aggression, that has no immunologic memory. Adaptive immunity, on the other hand, is antigen-dependent and antigen-specific; it has the capacity for memory, which enables the host to mount a more rapid and efficient immune response upon subsequent exposure to the antigen. There is a great deal of synergy between the adaptive immune system and its innate counterpart, and defects in either system can provoke illness or disease, such as inappropriate inflammation, autoimmune diseases, immunodeficiency disorders and hypersensitivity reactions. This article provides a practical overview of innate and adaptive immunity, and describes how these host defense mechanisms are involved in both heath and illness.

There are continuous advances in our current understanding of the immune system and how it functions to protect the body from infection. Given the complex nature of this subject, it is beyond the scope of this article to provide an in-depth review of all aspects of immunology. Rather, the purpose of this article is to provide medical students, medical residents, primary-care practitioners and other healthcare professionals with a basic introduction to the main components and function of the immune system and its role in both health and disease. This article will also serve as a backgrounder to the immunopathological disorders discussed in the remainder of this supplement.

The immune system: innate and adaptive immunity

The immune system refers to a collection of cells, chemicals and processes that function to protect the skin, respiratory passages, intestinal tract and other areas from foreign antigens, such as microbes (organisms such as bacteria, fungi, and parasites), viruses, cancer cells, and toxins. Beyond, the structural and chemical barriers which protect us from infection, the immune system can be simplistically viewed as having two “lines of defense”: innate immunity and adaptive immunity. Innate immunity represents the first line of defense to an intruding pathogen. It is an antigen-independent (non-specific) defense mechanism that is used by the host immediately or within hours of encountering an antigen. The innate immune response has no immunologic memory and, therefore, it is unable to recognize or “memorize” the same pathogen should the body be exposed to it in the future. Adaptive immunity, on the other hand, is antigen-dependent and antigen-specific and, therefore, involves a lag time between exposure to the antigen and maximal response. The hallmark of adaptive immunity is the capacity for memory which enables the host to mount a more rapid and efficient immune response upon subsequent exposure to the antigen. Innate and adaptive immunity are not mutually exclusive mechanisms of host defense, but rather are complementary, with defects in either system resulting in host vulnerability or inappropriate responses [ 1 – 3 ].

Innate immunity

Innate immunity can be viewed as comprising four types of defensive barriers: anatomic (skin and mucous membrane), physiologic (temperature, low pH and chemical mediators), endocytic and phagocytic, and inflammatory. Table  1 summarizes the non-specific host-defense mechanisms for each of these barriers. Cells and processes that are critical for effective innate immunity to pathogens that evade the anatomic barriers have been widely studied. Innate immunity to pathogens relies on pattern recognition receptors (PRRs) which allow a limited range of immune cells to detect and respond rapidly to a wide range of pathogens that share common structures, known as pathogen associated molecular patterns (PAMPs). Examples of these include bacterial cell wall components such as lipopolysaccharides (LPS) and double-stranded ribonucleic acid (RNA) produced during viral infection.

Table 1

Summary of non-specific host-defense mechanisms for barriers of innate immunity [ 1 ]

An important function of innate immunity is the rapid recruitment of immune cells to sites of infection and inflammation through the production of cytokines and chemokines (small proteins involved in cell–cell communication and recruitment). Cytokine production during innate immunity mobilizes many defense mechanisms throughout the body while also activating local cellular responses to infection or injury. Key inflammatory cytokines released during the early response to bacterial infection are: tumour necrosis factor (TNF), interleukin 1 (IL-1) and interleukin 6 (IL-6). These cytokines are critical for initiating cell recruitment and the local inflammation which is essential for clearance of many pathogens. They also contribute to the development of fever. Dysregulated production of such inflammatory cytokines is often associated with inflammatory or autoimmune disease, making them important therapeutic targets.

The complement system is a biochemical cascade that functions to identify and opsonize (coat) bacteria and other pathogens. It renders pathogens susceptible to phagocytosis, a process by which immune cells engulf microbes and remove cell debris, and also kills some pathogens and infected cells directly. The phagocytic action of the innate immune response promotes clearance of dead cells or antibody complexes and removes foreign substances present in organs, tissues, blood and lymph. It can also activate the adaptive immune response through the mobilization and activation of antigen-presenting cells (APCs) (discussed later) [ 1 , 3 ].

Numerous cells are involved in the innate immune response such as phagocytes (macrophages and neutrophils), dendritic cells, mast cells, basophils, eosinophils, natural killer (NK) cells and innate lymphoid cells. Phagocytes are sub-divided into two main cell types: neutrophils and macrophages. Both of these cells share a similar function: to engulf (phagocytose) microbes and kill them through multiple bactericidal pathways. In addition to their phagocytic properties, neutrophils contain granules and enzyme pathways that assist in the elimination of pathogenic microbes. Unlike neutrophils (which are short-lived cells), macrophages are long-lived cells that not only play a role in phagocytosis, but are also involved in antigen presentation to T cells (see Fig.  1 ) [ 1 ].

Characteristics and function of cells involved in innate immunity [ 1 , 3 , 4 ]. *Dust cells (within pulmonary alveolus), histiocytes (connective tissue), Kupffer cells (liver), microglial cells (neural tissue), epithelioid cells (granulomas), osteoclasts (bone), mesangial cells (kidney)

Dendritic cells also phagocytose and function as APCs, initiating the acquired immune response and acting as important messengers between innate and adaptive immunity. Mast cells and basophils share many salient features with each other, and both are instrumental in the initiation of acute inflammatory responses, such as those seen in allergy and asthma. Mast cells also have important functions as immune “sentinel cells” and are early producers of cytokines in response to infection or injury. Unlike mast cells, which generally reside in the connective tissue surrounding blood vessels and are particularly common at mucosal surfaces, basophils reside in the circulation. Eosinophils are granulocytes that possess phagocytic properties and play an important role in the destruction of parasites that are often too large to be phagocytosed. Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma. Natural killer (NK) cells play a major role in the rejection of tumours and the destruction of cells infected by viruses. Destruction of infected cells is achieved through the release of perforins and granzymes (proteins that cause lysis of target cells) from NK-cell granules which induce apoptosis (programmed cell death) [ 4 ]. NK cells are also an important source of another cytokine, interferon-gamma (IFN-γ), which helps to mobilize APCs and promote the development of effective anti-viral immunity. Innate lymphoid cells (ILCs) play a more regulatory role. Depending on their type (i.e., ILC-1, ILC-2, ILC-3), they selectively produce cytokines such as IL-4, IFN-γ and IL-17 that help to direct the appropriate immune response to specific pathogens and contribute to immune regulation in that tissue.

The main characteristics and functions of the cells involved in the innate immune response are summarized in Fig.  1 .

Adaptive immunity

The development of adaptive immunity is aided by the actions of the innate immune system, and is critical when innate immunity is ineffective in eliminating infectious agents. The primary functions of the adaptive immune response are: the recognition of specific “non-self” antigens, distinguishing them from “self” antigens; the generation of pathogen-specific immunologic effector pathways that eliminate specific pathogens or pathogen-infected cells; and the development of an immunologic memory that can quickly eliminate a specific pathogen should subsequent infections occur [ 2 ]. Adaptive immune responses are the basis for effective immunization against infectious diseases. The cells of the adaptive immune system include: antigen-specific T cells, which are activated to proliferate through the action of APCs, and B cells which differentiate into plasma cells to produce antibodies.

T cells and APCs

T cells derive from hematopoietic stem cells in bone marrow and, following migration, mature in the thymus. These cells express a series of unique antigen-binding receptors on their membrane, known as the T-cell receptor (TCR). Each T cell expresses a single type of TCR and has the capacity to rapidly proliferate and differentiate if it receives the appropriate signals. As previously mentioned, T cells require the action of APCs (usually dendritic cells, but also macrophages, B cells, fibroblasts and epithelial cells) to recognize a specific antigen.

The surfaces of APCs express a group of proteins known as the major histocompatibility complex (MHC). MHC are classified as either class I (also termed human leukocyte antigen [HLA] A, B and C) which are found on all nucleated cells, or class II (also termed HLA DP, DQ and DR) which are found only on certain cells of the immune system, including macrophages, dendritic cells and B cells. Class I MHC molecules present endogenous (intracellular) peptides, while class II molecules on APCs present exogenous (extracellular) peptides to T cells. The MHC protein displays fragments of antigens (peptides) when a cell is infected with an intracellular pathogen, such as a virus, or has phagocytosed foreign proteins or organisms [ 2 , 3 ].

T cells have a wide range of unique TCRs which can bind to specific foreign peptides. During the development of the immune system, T cells that would react to antigens normally found in our body are largely eliminated. T cells are activated when they encounter an APC that has digested an antigen and is displaying the correct antigen fragments (peptides) bound to its MHC molecules. The opportunities for the right T cells to be in contact with an APC carrying the appropriate peptide MHC complex are increased by the circulation of T cells throughout the body (via the lymphatic system and blood stream) and their accumulation (together with APCs) in lymph nodes. The MHC-antigen complex activates the TCR and the T cell secretes cytokines which further control the immune response. This antigen presentation process stimulates T cells to differentiate primarily into either cytotoxic T cells (CD8+ cells) or T-helper (Th) cells (CD4+ cells) (see Fig.  2 ). CD8+ cytotoxic T cells are primarily involved in the destruction of cells infected by foreign agents, such as viruses, and the killing of tumour cells expressing appropriate antigens. They are activated by the interaction of their TCR with peptide bound to MHC class I molecules. Clonal expansion of cytotoxic T cells produces effector cells which release substances that induce apoptosis of target cells. Upon resolution of the infection, most effector cells die and are cleared by phagocytes. However, a few of these cells are retained as memory cells that can quickly differentiate into effector cells upon subsequent encounters with the same antigen [ 2 , 3 ].

Adaptive immunity: T-cell and B-cell activation and function. APC antigen-presenting cell, TCR T-cell receptor, MHC major histocompatibility complex

(figure adapted from images available at: http://en.wikipedia.org/wiki/Image:B_cell_activation.png and http://commons.wikimedia.org/wiki/Image:Antigen_presentation.svg )

CD4+ Th cells play an important role in establishing and maximizing the immune response. These cells have no cytotoxic or phagocytic activity, and cannot directly kill infected cells or clear pathogens. However, they “mediate” the immune response by directing other cells to perform these tasks and regulate the type of immune response that develops. Th cells are activated through TCR recognition of antigen bound to class II MHC molecules. Once activated, Th cells release cytokines that influence the activity of many cell types, including the APCs that activate them.

Several types of Th cell responses can be induced by an APC, with Th1, Th2 and Th17 being the most frequent. The Th1 response is characterized by the production of IFN-γ which activates the bactericidal activities of macrophages and enhances anti-viral immunity as well as immunity to other intracellular pathogens. Th1-derived cytokines also contribute to the differentiation of B cells to make opsonizing antibodies that enhance the efficiency of phagocytes. An inappropriate Th1 response is associated with certain autoimmune diseases.

The Th2 response is characterized by the release of cytokines (IL-4, 5 and 13) which are involved in the development of immunoglobulin E (IgE) antibody-producing B cells, as well as the development and recruitment of mast cells and eosinophils that are essential for effective responses against many parasites. In addition, they enhance the production of certain forms of IgG that aid in combatting bacterial infection. As mentioned earlier, mast cells and eosinophils are instrumental in the initiation of acute inflammatory responses, such as those seen in allergy and asthma. IgE antibodies are also associated with allergic reactions (see Table  2 ). Therefore, an imbalance of Th2 cytokine production is associated with the development of atopic (allergic) conditions. Th17 cells have been more recently described. They are characterized by the production of cytokines of the IL-17 family, and are associated with ongoing inflammatory responses, particularly in chronic infection and disease. Like cytotoxic T cells, most Th cells will die upon resolution of infection, with a few remaining as Th memory cells [ 2 , 3 ].

Table 2

Major functions of human Ig antibodies [ 5 ]

A subset of the CD4+ T cell, known as the regulatory T cell (T reg), also plays a role in the immune response. T reg cells limit and suppress immune responses and, thereby, may function to control aberrant responses to self-antigens and the development of autoimmune disease. T reg cells may also help in the resolution of normal immune responses, as pathogens or antigens are eliminated. These cells also play a critical role in the development of “immune tolerance” to certain foreign antigens, such as those found in food.

B cells arise from hematopoietic stem cells in the bone marrow and, following maturation, leave the marrow expressing a unique antigen-binding receptor on their membrane. Unlike T cells, B cells can recognize antigens directly, without the need for APCs, through unique antibodies expressed on their cell surface. The principal function of B cells is the production of antibodies against foreign antigens which requires their further differentiation [ 2 , 3 ]. Under certain circumstances, B cells can also act as APCs.

When activated by foreign antigens to which they have an appropriate antigen specific receptor, B cells undergo proliferation and differentiate into antibody-secreting plasma cells or memory B cells (see Fig.  2 ). Memory B cells are “long-lived” survivors of past infection and continue to express antigen-binding receptors. These cells can be called upon to respond quickly by producing antibodies and eliminating an antigen upon re-exposure. Plasma cells, on the other hand, are relatively short-lived cells that often undergo apoptosis when the inciting agent that induced the immune response is eliminated. However, these cells produce large amounts of antibody that enter the circulation and tissues providing effective protection against pathogens.

Given their function in antibody production, B cells play a major role in the humoral or antibody-mediated immune response (as opposed to the cell-mediated immune response, which is governed primarily by T cells) [ 2 , 3 ].

Antibody-mediated vs. cell-mediated immunity

Antibody-mediated immunity is the branch of the acquired immune system that is mediated by B-cell-antibody production. The antibody-production pathway begins when the B cell’s antigen-binding receptor recognizes and binds to antigen in its native form. Local Th cells secrete cytokines that help the B cell multiply and direct the type of antibody that will be subsequently produced. Some cytokines, such as IL-6, help B-cells to mature into antibody-secreting plasma cells. The secreted antibodies bind to antigens on the surface of pathogens, flagging them for destruction through complement activation, opsonin promotion of phagocytosis and pathogen elimination by immune effector cells. Upon elimination of the pathogen, the antigen–antibody complexes are cleared by the complement cascade (see Fig.  2 ) [ 2 ].

Five major types of antibodies are produced by B cells: IgA, IgD, IgE, IgG and IgM. IgG antibodies can be further subdivided into structurally distinct subclasses with differing abilities to fix complement, act as opsonins, etc. The major classes of antibodies have substantially different biological functions and recognize and neutralize specific pathogens. Table  2 summarizes the various functions of the five Ig antibodies [ 5 ].

Antibodies play an important role in containing virus proliferation during the acute phase of infection. However, they are not generally capable of eliminating a virus once infection has occurred. Once an infection is established, cell-mediated immune mechanisms are most important in host defense against most intracellular pathogens.

Cell-mediated immunity does not involve antibodies, but rather protects an organism through [ 2 ]:

• The activation of antigen-specific cytotoxic T cells that induce apoptosis of cells displaying foreign antigens or derived peptides on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumour antigens;
• The activation of macrophages and NK cells, enabling them to destroy intracellular pathogens; and
• The stimulation of cytokine (such as IFNγ) production that further mediates the effective immune response.

Cell-mediated immunity is directed primarily at microbes that survive in phagocytes as well as those that infect non-phagocytic cells. This type of immunity is most effective in eliminating virus-infected cells and cancer cells, but can also participate in defending against fungi, protozoa, cancers, and intracellular bacteria. Cell-mediated immunity also plays a major role in transplant rejection.

Passive vs. active immunization

Acquired immunity is attained through either passive or active immunization. Passive immunization refers to the transfer of active humoral immunity, in the form of “ready-made” antibodies, from one individual to another. It can occur naturally by transplacental transfer of maternal antibodies to the developing fetus, or it can be induced artificially by injecting a recipient with exogenous antibodies that are usually manufactured for this purpose and that are targeted to a specific pathogen or toxin. The latter is used when there is a high risk of infection and insufficient time for the body to develop its own immune response, or to reduce the symptoms of chronic or immunosuppressive diseases.

Active immunization refers to the production of antibodies against a specific antigen or pathogen after exposure to the antigen. It can be acquired through either natural infection with a microbe or through administration of a vaccine that can consist of attenuated (weakened) pathogens, inactivated organisms or specific proteins or carbohydrates known to induce immunity. Effective active immunization often requires the use of “adjuvants” which improve the ability of the immune system to respond to antigen injection.

Immunopathology

As mentioned earlier, defects or malfunctions in either the innate or adaptive immune response can provoke illness or disease. Such disorders are generally caused by an overactive immune response (known as hypersensitivity reactions), an inappropriate reaction to self (known as autoimmunity) or ineffective immune responses (known as immunodeficiency).

Hypersensitivity reactions

Hypersensitivity reactions refer to undesirable responses produced by the normal immune system. There are four types of hypersensitivity reactions [ 6 , 7 ]:

• Type I: immediate hypersensitivity.
• Type II: cytotoxic or antibody-dependent hypersensitivity.
• Type III: immune complex disease.
• Type IV: delayed-type hypersensitivity.

Type I hypersensitivity is the most common type of hypersensitivity reaction. It is an allergic reaction provoked by re-exposure to a specific type of antigen, referred to as an allergen. Unlike the normal immune response, the type I hypersensitivity response is characterized by the secretion of IgE by plasma cells. IgE antibodies bind to receptors on the surface of tissue mast cells and blood basophils, causing them to be “sensitized”. Later exposure to the same allergen cross-links the bound IgE on sensitized cells resulting in degranulation and the secretion of active mediators such as histamine, leukotrienes, and prostaglandins that cause vasodilation and smooth-muscle contraction of the surrounding tissue. Common environmental allergens inducing IgE-mediated allergies include pet (e.g., cat, dog, horse) epithelium, pollen, house dust mites, and molds. Food allergens are also a common cause of type I hypersensitivity reactions, however, these types of reactions are more frequently seen in children than adults. Treatment of type I reactions generally involves trigger avoidance, and in the case of inhaled allergens, pharmacological intervention with bronchodilators, antihistamines and anti-inflammatory agents. Some types of allergic disease can be treated with immunotherapy (see Allergen-specific Immunotherapy article in this supplement). Severe cases of type 1 hypersensitivity (anaphylaxis) may require immediate treatment with epinephrine.

Type II hypersensitivity reactions are rare and take anywhere from 2 to 24 h to develop. These types of reactions occur when IgG and IgM antibodies bind to the patient’s own cell-surface molecules, forming complexes that activate the complement system. This, in turn, leads to opsonization, red blood cell agglutination (process of agglutinating or “clumping together”), cell lysis and death. Some examples of type II hypersensitivity reactions include: erythroblastosis fetalis, Goodpasture syndrome, and autoimmune anemias.

Type III hypersensitivity reactions occur when IgG and IgM antibodies bind to soluble proteins (rather than cell surface molecules as in type II hypersensitivity reactions) forming immune complexes that can deposit in tissues, leading to complement activation, inflammation, neutrophil influx and mast cell degranulation. This type of reaction can take days, or even weeks, to develop and treatment generally involves anti-inflammatory agents and corticosteroids. Examples of type III hypersensitivity reactions include systemic lupus erythematosus (SLE), serum sickness and reactive arthritis.

Unlike the other types of hypersensitivity reactions, type IV reactions are cell-mediated and antibody-independent. They are the second most common type of hypersensitivity reaction and usually take 2 or more days to develop. These types of reactions are caused by the overstimulation of T cells and monocytes/macrophages which leads to the release of cytokines that cause inflammation, cell death and tissue damage. In general, these reactions are easily resolvable through trigger avoidance and the use of topical corticosteroids. An example of this is the skin response to poison ivy.

A brief summary of the four types of hypersensitivity reactions is provided in Table  3 .

Table 3

Types of hypersensitivity reactions [ 6 , 7 ]

Autoimmunity

Autoimmunity involves the loss of normal immune homeostasis such that the organism produces an abnormal response to its own tissue. The hallmark of autoimmunity is the presence of self-reactive T cells, auto-antibodies, and inflammation. Prominent examples of autoimmune diseases include: Celiac disease, type 1 diabetes mellitus, Addison’s disease and Graves’ disease [ 8 ].

Inflammation

Poorly regulated inflammatory responses and tissue damage as a result of inflammation are often immunopathological features. Defects in immune regulation are associated with many chronic inflammatory diseases, including: rheumatoid arthritis, psoriasis, inflammatory bowel disease and asthma. Classical features of inflammation are heat, redness, swelling and pain. Inflammation can be part of the normal host response to infection and a required process to rid the body of pathogens, or it may become uncontrolled and lead to chronic inflammatory disease. The overproduction of inflammatory cytokines (such as TNF, IL-1 and IL-6) as well as the recruitment of inflammatory cells (such as neutrophils and monocytes) through the function of chemokines are important drivers of the inflammatory process. Additional mediators produced by recruited and activated immune cells induce changes in vascular permeability and pain sensitivity.

Immunodeficiency

Immunodeficiency refers to a state in which the immune system’s ability to fight infectious disease is compromised or entirely absent. Immunodeficiency disorders may result from a primary genetic defect (primary immunodeficiency—see Primary Immunodeficiency article in this supplement) which can effect either innate or acquired immune function through inhibition of selected immune cells or pathways, or it may be acquired from a secondary cause (secondary immunodeficiency), such as viral or bacterial infections, malnutrition, autoimmunity or treatment with drugs that induce immunosuppression. Certain diseases can also directly or indirectly impair the immune system such as leukemia and multiple myeloma. Immunodeficiency is also the hallmark of acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV). HIV directly infects Th cells and also impairs other immune system responses indirectly [ 9 , 10 ].

Innate immunity is the first immunological, non-specific mechanism for fighting against infections. This immune response is rapid, occurring minutes or hours after aggression and is mediated by numerous cells including phagocytes, mast cells, basophils and eosinophils, as well as the complement system. Adaptive immunity develops in conjunction with innate immunity to eliminate infectious agents; it relies on the tightly regulated interplay between T cells, APCs and B cells. A critical feature of adaptive immunity is the development of immunologic memory or the ability of the system to learn or record its experiences with various pathogens, leading to effective and rapid immune responses upon subsequent exposure to the same or similar pathogens. A brief overview of the defining features of innate and adaptive immunity are presented in Table  4 .

Table 4

Overview of the defining features of innate and adaptive immunity [ 1 ]

There is a great deal of synergy between the adaptive immune system and its innate counterpart, and defects in either system can lead to immunopathological disorders, including autoimmune diseases, immunodeficiencies and hypersensitivity reactions. The remainder of this supplement will focus on the appropriate diagnosis, treatment and management of some of these more prominent disorders, particularly those associated with hypersensitivity reactions.

Declarations

Authors’ contributions All authors wrote and/or edited sections of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

The authors would like to extend special thanks to Dr. Francesca Antonetti whose accredited online course entitled “An Introduction to Immunology” provided the foundation and framework for this article. This informative, entry-level course can be accessed through the Excellence in Medical Education (EXCEMED) website at: https://www.excemed.org .

This article is an update to the article entitled, An Introduction to Immunology and Immunopathology, that originally appeared in the supplement, Practical Guide to Allergy and Immunology in Canada, which was published in Allergy, Asthma & Clinical Immunology in 2011 (available at: https://aacijournal.biomedcentral.com/articles/supplements/volume-7-supplement-1 ).

The authors would like to thank Julie Tasso for her editorial services and assistance in the preparation of this manuscript.

Competing interests

Dr. Jean S. Marshall has no competing interests to disclose. Dr. Richard Warrington is the past president of the Canadian Society of Allergy & Clinical Immunology and Editor-in-Chief of Allergy, Asthma & Clinical Immunology. He has received consulting fees and honoraria from Nycomed, CSL Behring, Talecris, Grifols, Novartis and Shire. Dr. Wade Watson is an associate editor of Allergy, Asthma & Clinical Immunology. Dr. Harold Kim is Vice President of the Canadian Society of Allergy and Clinical Immunology, Past President of the Canadian Network for Respiratory Care, and Co-chief Editor of Allergy, Asthma and Clinical Immunology. He has received consulting fees and honoraria for continuing medical education from AstraZeneca, Aralez, Boehringer Ingelheim, CSL Behring, Kaleo, Merck, Novartis, Pediapharm, Sanofi, Shire and Teva.

Availability of data and materials

Consent for publication.

Not applicable.

Ethics approval and consent to participate

Ethics approval and consent to participate are not applicable to this review article.

Publication of this supplement has been supported by AstraZeneca, Boehringer Ingelheim, CSL Behring Canada Inc., MEDA Pharmaceuticals Ltd., Merck Canada Inc., Pfizer Canada Inc., Shire Pharma Canada ULC, Stallergenes Greer Canada, Takeda Canada, Teva Canada Innovation, Aralez Tribute and Pediapharm.

About this supplement

This article has been published as part of Allergy, Asthma & Clinical Immunology Volume 14 Supplement 2, 2018: Practical guide for allergy and immunology in Canada 2018. The full contents of the supplement are available online at https://aacijournal.biomedcentral.com/articles/supplements/volume-14-supplement-2 .

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Therapeutic Itineraries during the Ebola Epidemic in the Democratic Republic of Congo

Tiaman Diarra 1 , Joseph Okeibunor 2* , Bailo Diallo 2 , Nkechi Onyeneho 3 , Barry Rodrigue 2 , Michel N’da Konan Yao 2 , Zabulon Yoti 2 , Soce Fall 2 1 Independent Consultant, Mali 2 World Health Organization, Switzerland 3 University of Nigeria, Nsukka

While treating a disease, patients or their relatives make decisions to pursue different therapeutic options, and various stages are involved in searching for a cure. This paper explored the pattern of health-seeking in the Democratic Republic of Congo (DRC) during the 10 th Ebola virus disease (EVD) outbreak. Eight hundred randomly selected adults were surveyed using a questionnaire. Qualitative data were also collected through in-depth interviews with 17 community leaders and 20 focus group discussions with community members. The results showed that modern healthcare facilities are not usually considered the first option for treatment. The therapeutic journey generally begins with the patients, who treat themselves based on the information they know about the disease and the resources they have at their disposal. However, if the disease is not cured through self-medication, then patients or their relatives will visit a pharmacy. Patients request medication they know to be effective in treating the disease, and relatives can also assist in obtaining medication in the case of immobile patients. Pharmacies commonly sell the medication to patients or their relatives without a medical prescription.

Epidemic Response amidst Insecurity: Addressing the Ebola Virus Epidemic in the Provinces of North Kivu and Ituri

Tiaman Diarra 1 , Joseph Okeibunor 2* , Bailo Diallo 2 , Nkechi Onyeneho 3 , Barry Rodrigue 2 , Michel N’da Konan Yao 2 , Zabulon Yoti 2 , Mamoudou Harouna Djingarey 4 , Soce Fall 2 , Abdou Salam Gueye 2 1 Independent Consultant, Mali 2 World Health Organization, Switzerland 3 University of Nigeria, Nsukka

This paper examines the impact of insecurity on the management of the Ebola virus disease epidemic in the Democratic Republic of the Congo provinces of North Kivu and Ituri. In these provinces, insecurity has been one of the biggest obstacles in the response to the Ebola outbreak. When the epidemic began, these provinces were already insecure—creating unfavorable circumstances for implementing epidemic response activities. While the ninth epidemic in the Equateur province was brought under control in record time, the same was not true for the tenth epidemic in North Kivu and Ituri. Since the epidemic began, teams were organized to address all aspects of the response. These response teams conducted extensive fieldwork, including epidemiological surveillance, risk communication and community involvement, infection prevention and control, vaccination, dignified and safe burials, care at transit centers and Ebola treatment centers, and medical and psychosocial care for the recovered. They faced confrontational reactions from the communities, which jeopardized their security. The insecure state of the provinces led to the destruction and damage of infrastructure, including healthcare facilities, which affected the ability of rescue teams to access people needing care as well as the resources they needed to care for the ill. Worse yet, the insecurity took other forms, including threatening and kidnapping members of the response teams, lodging protests against the response activities in towns or health zones, committing violence against teams responsible for safe and dignified burials, instigating altercations between community members and members of the response team, and encouraging general resistance by the population. This level of insecurity interrupted or even halted response activities in some areas—sometimes for more than two weeks, decreasing the efficiency of the response teams, particularly in monitoring contacts due to the inability to access certain communities. Additionally, certain acts of protest, such as community members handling bodies as a demonstration of their opposition to safe and dignified burials, likely intensified disease spread. However, the involvement of community leaders, at least, made dialogue and negotiation possible between the response teams and community members, as such efforts led to communities contributing to the security of personnel involved in the fight against the Ebola epidemic in North Kivu and Ituri provinces.

The Impact of the Ebola Virus Disease Epidemic among Women in the Provinces of North Kivu and Ituri in the Democratic Republic of the Congo

Nkechi G. Onyeneho 1* , Ngozi Idemili Aronu 1 , Ijeoma Igwe 1 , Joseph Okeibunor 2 , Tieman Diarra 3 , Julienne Ngoudougou Anoko 2 , Mamoudou Harouna Djingarey 4 , Zabulon Yoti 2 , Dick Chamla, Abdou Salam Gueye 1 University of Nigeria, Nsukka 2 World Health Organization, Switzerland 3 Independent Consultant, Mali 4 Independent Public Health Expert, Niger

Although an outbreak of the Ebola virus disease affects an entire population, women are more susceptible to the virus than men. Throughout the outbreaks of the Ebola virus disease in Central and West Africa, women have been impacted more significantly. Generally, over half of those who become ill are women. The situation is the same in terms of mortality. Further, the outcomes of the epidemic negatively affect women socially, as many become the heads of households following the loss of their spouses, which burdens them with new responsibilities. Women’s access to health services is also lowered, as the epidemic usually leads to fewer healthcare workers, impacting gynecological assistance. Consequently, women are more exposed to health problems, particularly during pregnancy. Several factors contribute to the greater exposure of women to the Ebola virus disease during an epidemic. First, female healthcare workers are at the frontline of the fight against the virus. Second, women’s duties in the domestic context increase their exposure to contamination, as they look after children and care for sick household members. Finally, women are responsible for several community duties such as public tasks and rituals. In the case of rituals, women undertake tasks such as undressing, washing, and dressing the deceased. Likewise, they engage in agricultural work and grocery shopping locally, as well as at cross-border markets. They also manage domestic chores such as fetching water in public places. Additionally, women have less access to information on the disease and its prevention and are thus more vulnerable. However, women’s vulnerability is less visible, since information on the epidemic and response is not gender specific. This is true for the number of suspected cases, confirmed cases, vaccinated people, alerts, contacts, contacts followed up, and screened travelers. It is therefore crucial to highlight the importance of gender in the response to the Ebola virus disease epidemic, as women are the primary victims.

Two Obstacles in Response Efforts to the Ebola Epidemic in the Provinces of North Kivu and Ituri in the Democratic Republic of the Congo: Denial of and Rumors about the Disease

Nkechi G. Onyeneho 1* , Ngozi Idemili Aronu 1 , Ijeoma Igwe 1 , Joseph Okeibunor 2 , Tieman Diarra 3 , Bailo Diallo 2 , Bairo Hamadou 2 , Barry Rodrigue 2 , Mamoudou Harouna Djingarey 4 , Zabulon Yoti 2 , Michel N’da Konan Yao 2 , Soce Fall 2 , Dick Chamla 2 , Abdou Salam Gueye 2 1 University of Nigeria, Nsukka 2 World Health Organization, Switzerland 3 Independent Consultant, Mali 4 Independent Public Health Expert, Niger

Denial and rumors are two major obstacles impairing the implementation of activities in response to the Ebola virus disease (EVD) epidemic. This study investigated the roles of denial and rumors, among other challenges, in complicating the response to the EVD outbreak in the North Kivu and Ituri provinces of the Democratic Republic of the Congo. A total of 800 randomly selected respondents were surveyed using a structured questionnaire. In-depth interviews were conducted with 17 community religious and opinion leaders, as well as Ebola survivors. Furthermore, 20 focus group discussions were conducted with adult and youth male and female participants, and health care workers. The results revealed that the existence of the disease is widely denied by many, including political leaders, village chiefs, neighborhood chiefs, street chiefs, avenue chiefs, and members of the general population. These individuals generally consider the EVD to be the result of a misbehavior or a curse; consequently, the general population, including community members, teachers, and even health care professionals, refuse to comply with the authorities’ strategies to fight the epidemic. Rumors are another obstacle in response efforts. Rumors pertaining to the denial of the existence of the EVD, as well as the epidemic, Ebola treatment centers, hospitals, vaccines, and safe and dignified burials have been identified. Rumors about the EVD and the response, spread by clerics, traditional therapists, men, and women, including healthcare professionals in focus group discussions, portrayed the EVD as an invention, as if the virus had been created. The response to the EVD has been marked by these two constraints, which have often hindered the involvement of community members in the fight against the disease.

Survivors and the Response to the Ebola Virus Disease in the Provinces of North Kivu and Ituri in the Democratic Republic of Congo

Joseph Okeibunor 1* , Tieman Diarra 2 , Nkechi Onyeneho 3 , Bailo Diallo 1 , Michel N’da Konan Yao 1 , Mamoudou Harouna Djingarey 4 , Zabulon Yoti 1 , Soce Fall 3 , Dick Chamla 1 , Abdou Salam Gueye 1 1 World Health Organization, Switzerland 2 Independent Consultant, Mali 3 University of Nigeria, Nsukka 4 Independent Public Health Expert, Niger

We explored issues around the integration of survivors in communities and the implications of the Ebola Virus Disease (EVD) response in the Democratic Republic of Congo (DRC). We conducted a survey with 800 randomly selected respondents using a structured questionnaire. Respondents were persons aged 18 years and above. Focus group discussions (FGDs) and in-depth interviews (IDIs) were employed to obtain contextual data on the issues. Community leaders, health workers, and response pillar leads engaged in IDIs, while community members were involved in FGDs. The results revealed that the survivors suffered stigmatization and, upon return to the communities, were avoided by the community members due to fear of contamination. Some thought that the survivors should be supported in adjusting to the community, while some recommended engaging the survivors in EVD response activities.

Exploring Alternative Care Platforms for Symptomatic People in the Fight against the Ebola Virus Disease Outbreak

Nkechi G. Onyeneho 1* , Ngozi Idemili Aronu 1 , Ijeoma Igwe 1 , Joseph Okeibunor 2 , Tieman Diarra 3 , Bailo Diallo 2 , Bairo Hamadou 2 , Barry Rodrigue 2 , Mamoudou Harouna Djingarey 4 , Zabulon Yoti 2 , Michel N’da Konan Yao 2 , Soce Fall 2 1 University of Nigeria, Nsukka 2 World Health Organization, Switzerland 3 Independent Consultant, Mali 4 Independent Public Health Expert, Niger

Treatment centers (TCs) are the only locations designed to care for people with Ebola virus disease (EVD) symptoms. These people and their families are held at a TC as soon as they arrive at an Ebola treatment center (ETC); however, some people escape from TCs. This paper explored alternative care platforms for symptomatic people in the fight against the EVD outbreak in the Democratic Republic of Congo. Eight hundred randomly selected adults aged 18 years and above were surveyed with a uniform set of structured questionnaires. In-depth interviews were conducted with 20 community/opinion leaders, while focus group discussions were held with community members who were not involved in the questionnaire study. Our findings demonstrated that people who were suspected of having EVD preferred to be treated discreetly and at home, and were more willing to be tested at home than at a TC. People were afraid of being stigmatized if the TC exposed their admittance to the general public. This article proposes an alternative to the TCs. We suggest a temporary containment facility within the community, such as a room in the suspected person’s home. However, this requires negotiation between the response team and community members, with the latter having a significant responsibility in caring for their symptomatic relatives. The place or room for domestic temporary isolation should be chosen discreetly and placed far from the view of others. Community members will, thus, bear more responsibility for what happens while the patient is in isolation. The temporary containment area will assist in decentralizing the treatment of those with EVD symptoms. Its implementation will contribute to greater accountability of community members in the fight against EVD.

Traditional therapists in Ebola virus disease outbreak response: Lessons learned from the fight against the Ebola virus disease epidemic in North Kivu and Ituri, Democratic Republic of the Congo

Nkechi G. Onyeneho 1* , Ngozi Idemili Aronu 1 , Ijeoma Igwe 1 , Joseph Okeibunor 2 , Tieman Diarra 3 , Julienne Ngoudougou Anoko 2, Mamoudou Harouna Djingarey 4 , Zabulon Yoti 2 1 University of Nigeria, Nsukka 2 World Health Organization 3 Independent Consultant, Mali 4 Independent Public Health Expert, Niger

Traditional healers co-exist with orthodox medicine, especially in cases with perceived supernatural causes and during outbreaks of infectious diseases like the Ebola virus disease (EVD) in the North Kivu and Ituri provinces in the Democratic Republic of the Congo (DRC). In this study, we examined the role and potential of involving traditional healers in the national response to the Ebola virus disease outbreak in the DRC. Seventeen community leaders and 20 traditional healers were interviewed. The traditional healers managed symptoms with herbs and were not inclined to refer cases to orthodox healthcare facilities because of their confidence in their ability to handle cases with supernatural causes. The community leaders attested to the acceptance of the traditional healers in the communities, which they attributed to the efficacy of traditional healing, its uncomplicated treatment process, cause of the prolonged cough, as well as cost and the need for secrecy. Traditional healers can be educated to promptly refer cases to Ebola treatment centers for timely diagnosis and appropriate treatment.

Involvement of Civil Society Organizations and Other Community Groups in the Response to the Ebola Virus Disease Outbreak in the North Kivu and Ituri Provinces of the Democratic Republic of Congo

Tiaman Diarra 1 , Joseph Okeibunor 2 , Bailo Diallo 2 , Nkechi Onyeneho 3 , Barry Rodrigue 2 , Michel N’da Konan Yao 2 , Zabulon Yoti 2 , Soce Fall 2 1 Independent Consultant, Mali 2 World Health Organization 3 University of Nigeria, Nsukka

We reviewed the involvement of civil society organizations as well as other community level organizations and structures in the response to the Ebola Virus Disease (EVD) outbreak in the Democratic Republic of Congo. A total of 800 randomly selected adults were surveyed using a uniform set of structured questionnaires. An in-depth interview guide was employed to collect information from community members and religious leaders, while focus group discussions were held with community members. The results revealed some involvement of the different organizations in the communities in the response to the EVD outbreak. However, several challenges were encountered, namely security issues, poor awareness, and non-compliance to safety measures. The findings underscore that despite considerable experience over a long period with outbreaks in the DRC, people still need to be educated about the disease.

Community Involvement in Response to Ebola Virus Disease Epidemic in North Kivu and Ituri, Democratic Republic of Congo: A Mixed-Methods Study

Tiaman Diarra 1 , Joseph Okeibunor 2 , Bailo Diallo 2 , Nkechi Onyeneho 3 , Bairo Hamadou 2 , Michel N’da Konan Yao 2 , Zabulon Yoti 2 , Soce Fall 2 1 Independent Consultant, Mali 2 World Health Organization 3 University of Nigeria, Nsukka

We investigated the involvement of community members in response to the Ebola Virus Disease (EVD) epidemic in the North Kivu and Ituri provinces of the Democratic Republic of Congo. This cross-sectional study, conducted using mixed methods of data collection, included a uniformly structured questionnaire survey, which was administered to 800 randomly selected adults (aged ≥ 18 years). Further, we used qualitative tools of inquiry—focus group discussions (FGD) and in-depth interviews (IDI)—to guide the context of the information collected in the survey. Community leaders, religious leaders, and Ebola survivors were interviewed using the IDI guide, while young men (≤ 30 years), young women (≤30 years), adult community males (<30 years), and adult community females (<30 years) were in separate FGD sessions. The results revealed that the urban area was the most affected by the epidemic (79.2%) compared to 20.8% in rural areas. The χ 2 calculated was 18.183 (P<0.001). Community members exhibited varying degrees of involvement in response to the EVD epidemic in the two provinces. Community members were mostly engaged in information dissemination. However, they believe they could have contributed more if they had been fully engaged. These findings were derived from the qualitative data. The study contributes to evidence on how community involvement could help response to public health events globally, hence this study provides valuable insights for future public health interventions and response.

Perceptions and Rumors About the Ebola Virus Disease Vaccine in the Ituri and Kivu Provinces of the Democratic Republic of Congo

Ijeoma Igwe 1 , Nkechi Onyeneho 1 , Joseph C Okeibunor 2 , Michel N’da Konan Yao 2 , Tieman Diarra 3 , Mamoudou Harouna Djingarey 4 , Soce Fall 2 , Abdou Salam Gueye 2 1 University of Nigeria Nsukka 2 World Health Organization 3 Independent Consultant, Mali 4 Independent Scientist, Niger

Perceptions and rumors about vaccinations can contribute to vaccine hesitancy. This study aimed to examine perceptions and rumors about the Ebola vaccine during the 10 th Ebola Virus Disease outbreak in the Ituri and North Kivu provinces of the Democratic Republic of Congo. Eight hundred randomly selected respondents were surveyed with a uniform structured questionnaire. Further, we collected qualitative data through focus group discussions and using in-depth interview guides. Results revealed several misperceptions and rumors about the vaccine, which led to some level of vaccine hesitancy and refusal among the people. The acceptance rate of the vaccine was 67.3% (below the 80% threshold needed to create herd immunity in the population). More of the urban population (31.3%) than the rural population (10.4%) accepted the vaccine. Refusals were largely due to fear that the vaccine could activate other diseases in the body and could even kill. Some feared that it was a conspiracy of the government to reduce the population in the study area through forced fertility control and death, among other such concerns. In conclusion, these rumors increased mistrust, which challenged the efforts of the government and its partners to safeguard the health of the people.

Perceptions, Disease Representations, and Response Obstacles Regarding the Ebola Virus Disease Epidemic in the North Kivu and Ituri Provinces of the Democratic Republic of the Congo

Nkechi Onyeneho 1 , Joseph Okeibunor 2 , Ijeoma Igwe 1 , Ngozi Idemili Aronu 1 , Bailo Diallo 2 , Tiaman Diarra 3 , Barry Rodrigue 2 , Michel N’da Konan Yao 2 , Mamoudou HAROUNA DJINGAREY 4 , Soce Fall 2 1 University of Nigeria, Nsukka 2 World Health Organization 3 Independent Consultant, Mali 4 Independent Public Health Expert, Niger

We explored the perceptions and representations of diseases in the North Kivu and Ituri provinces of the Democratic Republic of Congo to identify perceived obstacles regarding responses to the country’s Ebola virus disease (EVD) outbreak using a mix-methods approach. We surveyed a representative sample including 800 adults aged 18 years and older, held in-depth interviews with 17 community leaders, and conducted 10 focus group discussions with community members (using same-sex interviewers/discussion leaders). The results revealed the existence of several health conditions among members of the two communities. Locals consider nearly 80 of these ailments as untreatable by orthodox medicines and methods, even when symptoms are similar to EVD. Creating awareness must be considered a critical goal of community education to further educate these populations about EVD and other health problems and their respective treatments.

Response of Healthcare Service Providers to the Ebola Virus Disease Epidemic in the Democratic Republic of Congo’s North Kivu and Ituri Provinces

Tieman Diarra 1 , Nkechi Onyeneho 2 , Joseph Okeibunor 3* , Bailo Dialloa 3 , Michel N’da Konan Yao 3 , Mamoudou Harouna Djingarey 4 , Soce Fall 3 , Dick Chamla, Abdou Salam Gueye 1 Independent Consultant, Mali 2 University of Nigeria, Nsukka 3 World Health Organization, Switzerland 4 Independent Public Health Expert, Niger

Healthcare service providers are crucial for effective responses to disease outbreaks. However, their performance is dependent on the level of system inputs, people’s perception of the system, and their willingness to use health services. This study investigated the functionality of health services and healthcare providers in the Democratic Republic of Congo during the tenth Ebola virus disease outbreak. It employed qualitative methods, including 24 in-depth interviews of healthcare providers and community leaders, and 12 focus-group discussions with community members. The responses showed that the staff did not desert the health centers and remained at their jobs. Throughout this research, only one case of abandonment of duty by a nurse was reported. The healthcare system thus played a major role in responding to the COVID-19 pandemic. However, the healthcare service providers faced several challenges. Suggestions are made to enhance the contributions of healthcare service and its providers to health emergencies in the future.

A Brief Review of the Monkeypox Outbreak: Transmission, Presentation, and Developments in Treatment and Vaccines

Aria Elahi 1 , Parker Alan Maddox 2 , Hassan Khuram 3 , Joshua Lewis 4 , Rahim Hirani 4* 1 The Robert Larner, MD College of Medicine at The University of Vermont 2 Sidney Kimmel Medical College at Thomas Jefferson University, PA, United States 3 Drexel University College of Medicine, PA, United States 4 New York Medical College School of Medicine, Valhalla NY, United States

The medical response to monkeypox(mpox) is a key demonstration of how COVID-19 remodeled the global response to viruses in the medical field. As a result of the 2019 pandemic, the 2022 mpox outbreak was met with mass production of vaccines, widely available PCR testing, and increased public health and research efforts. Easy access to vaccines such as the ACAM2000 and the JYNNEOS vaccines bolstered prevention while antivirals alleviated symptoms and shortened viral duration in at-risk patients. Various methods of detection have been developed for mpox over a short period with PCR currently being used in an attempt to isolate specific strains of the virus. In this brief review, we discuss its classical presentation, and detection and treatment strategies adapted to mitigate this public health risk.

Natriuretic Peptides in Clinical Practice: A Current Review

Deborah J.W. Lee 1 , Tar-Choon Aw 1,2,3* 1 Department of Laboratory Medicine, Changi General Hospital, Singapore 2 Clinical Senior Lecturer (Medicine), National University of Singapore (NUS) Yong Loo Lin School of Medicine, Singapore 3 Clinical Professor (Pathology), Duke-NUS Graduate School of Medicine, Singapore

Heart failure is a major clinical problem affecting 64 million people worldwide with a 5-year mortality rate of around 50%. Patients present to the emergency department with inability to breathe properly. Heart failure is an important condition not to be missed as accurate and early diagnosis or exclusion is crucial for timely intervention. Conventionally heart failure was regarded as congestion consequent to fluid accumulation. Currently heart failure is viewed as a complex heterogeneous entity encompassing severity (clinical versus sub-clinical), onset (acute versus chronic), vascular compartment involved (intra- versus extra-vascular), besides fluid accumulation (cardiopulmonary versus generalized). There is a myriad of biomarkers that reflect different parts of heart failure pathophysiology. However, only natriuretic peptides remain as the “gold standard” against which other biomarkers are compared. This review provides a current update on the utility of natriuretic peptides in clinical practice. We will provide a brief overview of natriuretic peptides, the assays, their clinical use in heart failure, some caveats for their use (age, chronic kidney disease, obesity, heart failure with preserved ejection fraction) and highlight some emerging applications.

Leflunomide Confers Rapid Recovery from COVID-19 and is Coupled with Temporal Immunologic Changes

Ada Alice Dona 1,2# , James F Sanchez 1# , Joycelynne M Palmer 3 , Timothy W. Synold 4 , Flavia Chiuppesi 5 , Sandra Thomas 2 , Enrico Caserta 1,2 , Mahmoud Singer 1,2 , Theophilus Tandoh 1,2 , Arnab Chowdhury 3 , Amrita Krishnan 1 , Michael Rosenzweig 1 , Don J Diamond 5 , Steven Rosen 1* , Flavia Pichiorri 1,2* , Sanjeet Dadwal 6* 1 Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 2 Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, CA 3 Department of Computational and Quantitative Sciences, Beckman Research Institute, City of Hope, Duarte, CA 4 Department of Cancer Biology, City of Hope, Duarte, CA 5 Department of Experimental Therapeutics, City of Hope, Duarte, CA 6 Department of Medicine, Division of Infectious Disease, City of Hope, Duarte, CA USA # These authors contributed equally to this work.

Background: Vaccines for SARS-CoV-2 have been considerably effective in reducing rates of infection and severe COVID-19. However, many patients, especially those who are immunocompromised due to cancer or other factors, as well as individuals who are unable to receive vaccines or are in resource-poor countries, will continue to be at risk for COVID-19. We describe clinical, therapeutic, and immunologic correlatives in two patients with cancer and severe COVID-19 who were treated with leflunomide after failing to respond to standard-of-care comprising remdesivir and dexamethasone. Both patients had breast cancer and were on therapy for the malignancy.

Methods: The protocol is designed with the primary objective to assess the safety and tolerability of leflunomide in treating severe COVID-19 in patients with cancer. Leflunomide dosing consisted of a loading dose of 100 mg daily for the first three days, followed by daily dosing, at the assigned dose level (Dose Level 1: 40 mg, Dose Level -1, 20 mg; Dose Level 2, 60 mg), for an additional 11 days. At defined intervals, serial monitoring of blood samples for toxicity, pharmacokinetics, and immunologic correlative studies were performed, as well as nasopharyngeal swabs for PCR analysis of SARS-CoV-2.

Results: Preclinically, leflunomide impaired viral RNA replication, and clinically, it led to a rapid improvement in the two patients discussed herein. Both patients completely recovered, with minimal toxicities; all adverse events experienced were considered unrelated to leflunomide. Single-cell mass-cytometry analysis showed that leflunomide increased levels of CD8+ cytotoxic and terminal effector T cells and decreased naïve and memory B cells.

Conclusions: With ongoing COVID-19 transmission and occurrence of breakthrough infections in vaccinated individuals, including patients with cancer, therapeutic agents that target both the virus and host inflammatory response would be helpful despite the availability of currently approved anti-viral agents. Furthermore, from an access to care perspective, especially in resource-limited areas, an inexpensive, readily available, effective drug with existing safety data in humans is relevant in the real-world setting.

Poor Prognosis in HBV-associated Hepatocellular Carcinoma After Successful Viral Suppression: A Case Series Highlighting a Need for a Cure

Salil Chowdhury 1 , Daniel Garrido 2 , Dina Halegoua-DeMarzio 3 , Christopher Roth 4 , Hie-Won Hann 3* 1 Thomas Jefferson University Hospital, Department of Internal Medicine, Philadelphia, PA 2 Cooper University Hospital, Digestive Health Institute, Camden, NJ 3 Thomas Jefferson University Hospital, Division of Gastroenterology and Hepatology, Philadelphia, PA 4 Thomas Jefferson University Hospital, Department of Radiology, Philadelphia PA

Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, with chronic hepatitis B virus (HBV) infection being an important risk factor for HCC. While nucleos(t)ide analog (NA) therapy has succeeded in suppressing HBV replication and decreasing the risk of HCC in patients with HBV infection, there remains a persistent risk of HCC in those patients. Furthermore, previous studies have highlighted worse survival in patients who developed HCC while on successful NA therapy compared to those who developed HCC without previous NA treatment.

 We conducted a long-term, retrospective case study in 5 patients observed between 10 and 25 years, to further explore the poor outcomes in patients with HBV-associated HCC with or without previous NA therapy. Our study highlights the aggression and recurrence of HCC in patients with HBV infection, well-suppressed on NA therapy. The results of our observation emphasize the need for early referral for liver transplantation in these select patients.

Implementation of Immunometabolism into Curricula, Scientific Societies, and Immunological Routine Diagnostics

Marc Roder 1 and Sascha Kahlfuss 1,2,3,4* 1 Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. 2 Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. 3 Health Campus Immunology, Infectiology and Inflammation (GCI 3 ), Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. 4 Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke-University, Magdeburg, Germany.

The energy metabolism was demonstrated to directly modulate immune cell function and thereby physiological and detrimental immune responses. In addition, the field of immunometabolism is vastly growing. However, yet there remain fundamental scientific questions in the field, which require the organization of national and international networks as well as the implementation of immunometabolism into curricula, scientific societies, and immunological routine diagnostics to hold the promise of personalized medicine to our patients within the next decade.

Soluble Complement Receptor 1 Therapeutics

Matthew P. Hardy 1* , Tony Rowe 1 , and Sandra Wymann 2 1 CSL, Bio21 Institute, Victoria, Australia 2 CSL, CSL Biological Research Centre, Bern, Switzerland

Human Complement Receptor 1 (CR1/CD35) is a potent negative regulator of the complement system. Its mechanism of action is through interaction with the complement activation fragments, C3b and C4b to mediate decay acceleration of the C3 and C5 convertase complexes as well as cleavage of both ligands into inactive fragments via cofactor activity. The result is inhibition of the classical, lectin, and alternative complement pathways. This article will focus on recombinant soluble forms of CR1 that have been generated as potential therapeutics for complement-mediated disorders. Specifically, we will review and contrast the in vitro and in vivo properties of: sCR1 (BRL55730/TP10/CDX-1135), the soluble full-length extracellular domain of human CR1; sCR1-sLe x (TP20), a glyco-engineered version of sCR1 additionally targeted to activated endothelium; APT070 (Mirococept), a CR1 fragment conjugated to a myristoylated peptide to enhance tissue targeting; and CSL040, a soluble truncated version of the CR1 extracellular domain which exhibits altered potency and pharmacokinetic properties as compared to the parental molecule. The data obtained from studies on the effects of these CR1-based molecules in animal models of disease and their therapeutic applications will also be discussed.

Serologic Response of SARS-CoV-2 mRNA-based Vaccines in Patients with Autoimmune Diseases

Kushal Gandhi 1# , Nathan Joshua Manales 1# , Asley Sanchez 1# , Srikanth Mukkera 1* , Anusha Ammu 1 , Janine Klar 1 , Alex Gibson 1 , Evangelina Santiago 2 , Ailena Mulkey 2 , Jammie Holland 2 , Maneesh Mannem 1 , Lakshmi P. Alahari 1 , and John Garza 1,3 1 School of Medicine, Texas Tech University Health Sciences Center (TTUHSC) at the Permian Basin, TX, USA 2 Clinical Research institute at the Permian Basin, Texas Tech University Health Sciences Center – Permian Basin, TX, USA 3 The University of Texas Permian Basin, Odessa, TX, USA # Authors contributed equally

Background: In the spring of 2021, coronavirus disease 2019 (COVID-19) vaccines were approved and distributed in the United States for the public to combat the COVID-19 pandemic, but their rapid development leaves some questions unanswered. Vaccine efficacy has always been a point of interest for individuals with rheumatological diseases that take immunosuppressants. This study investigates the vaccine efficacy of two COVID-19 mRNA-based vaccines, Moderna and Pfizer, in subjects in West Texas patients with autoimmune diseases.

Materials and Methods: Blood was collected from Texas Tech University employees who received both doses of COVID-19 vaccines within the past nine months. Subjects were separated into either a group with a known history of rheumatic disease (n=18) or those without (n=18). The samples were analyzed for serum immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM) levels using specific enzyme-linked immunoassay kits, and a neutralizing antibody test using a surrogate virus was conducted as well. Results were analyzed using the Mann-Whitney U test (unpaired, two-tailed).

Results: There was no significant difference in serum IgG and IgA levels between the control and rheumatologic disease groups, but there were significant differences in serum IgM levels. All subjects cleared the threshold for the neutralizing antibody test.

Conclusion: The relatively similar serum IgG levels and the 100% detection rate of effective neutralizing antibodies across both groups indicate promising signs of serological response for subjects with autoimmune conditions, but the relatively low serum IgA and IgM levels of the study the group warrants further investigation.

An Acute Inflammation with Special Expression of CD11 & CD4 Produces Abscopal Effect by Intratumoral Injection Chemotherapy Drug with Hapten in Animal Model

Baofa Yu, MD 1,2,3,4* , Qiang Fu, MS 3 , Yan Han, MS 3 , Jian Zhang 3 , Dong Chen，MD 3 1 Immuno Oncology Systems, Inc., San Diego, CA 92122, USA 2 TaiMei Baofa Cancer hospital, Dongping, Shandong Province, China, 271500 3 Jinan Baofa Cancer hospital, Jinan, Shandong Province, China，250000 4 Beijing Baofa Cancer Hospital, Beijing, China

Aim: To study the immunity reaction in tumor by intratumoral injection with a drug PYM and DNP, where it produces abscopal effect by the expression of immunological genes of tumor on home side (left side) while it brings a similar expression of same genes in tumor on opposite side (right side) of mice.

Method: Prepare each tumor on left side of 6 mice and injected intratumoral with a PYM+DNP and PYM control on day 1 and 7. Two day later of day 1, one of groups mice were inoculated with 0.2ml of H22 cells (10 5 /ml) again on the right underarms as opposite side for controls. On day15, the tumor on bilateral sides were excised for qPCR measurement.

Result:  It showed that inflammation with the expression of the CoL1a1, CD4, IL12aÂ, TGFb1Â, Elastin, Elastin, Cox2, CD11b/c, CD8, TNFa in different groups; The inflammation in both side of tumor but these is not only a increasing expression of Collal, CD4, IL12aÂ, TGFb1Â, Elastin, NFKB, Cox2, CD11c, CD8 and TNFa in tumor on home side of mice treated with PYM+DNP but also a similar an increasing expression of same genes in tumor on opposite side of mice which not treated at all. In the control group, it showed that inflammation without an expression of all factors related above immunity genes in both tumor on home treated with PYM only and opposite side of mice which not treated at all.

Conclusion: It indicated that PYM and hapten of DNP can induce an inflammation with stimulation of immunity reaction with the expression of the CoL1a1, CD4, IL12aÂ, TGFb1Â, Elastin, Elastin, Cox2, CD11b/c, CD8, TNFaÂ, which resulted in an abscopale effect. PYM can induce an inflammation but without expression of immuno genes, therefore, hapten is playing an important role with PYM in the special immunity reaction.

Protective and Susceptibility Effects of Human Leukocyte Antigen on Melanoma Prevalence and their Implications for Predicting Checkpoint Blockade Immunotherapy Outcomes

Lisa M. James 1,2,3 , Apostolos P. Georgopoulos 1,2,3,4* 1 The HLA Research Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA 2 Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA 3 Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA 4 Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

The association of Human Leukocyte Antigen (HLA) with melanoma has been well documented. Similarly, the outcome of checkpoint blockade immunotherapy (CBI) in melanoma depends, to some extent, on the HLA genotype of the patient. Although specific favorable (or unfavorable) HLA alleles for CBI outcome for melanoma have been identified, there is currently no reliable way to predict a positive, neutral or negative melanoma CBI outcome for other alleles. Here we used an immunogenetic epidemiological approach to identify HLA alleles whose frequency is negatively (or positively) associated with melanoma prevalence (protective or susceptibility alleles, respectively). The findings demonstrated that, indeed, HLA alleles that are negatively associated with melanoma prevalence in the population have been associated with good CBI outcome at the individual level and, conversely, HLA alleles that are positively associated with melanoma prevalence have been associated with poor CBI outcome in individuals. Given this good prediction of CBI cancer immunotherapy by specific immunogenetically discovered HLA alleles, we used this epidemiologic immunogenetic approach to identify more HLA Class I and II alleles protective (or susceptibility) for melanoma which would thus be good predictors of CBI outcomes in those cancers. This is a new approach to successfully (a) identify HLA protective or susceptibility alleles for melanoma, and (b) use that information in anticipating outcomes in CBI cancer immunotherapy.

Bispecific Antibodies as an Alternative to Antibody Cocktails for SARS-CoV-2: A Mini- Review

Gavin Yuen*, Saundarai Bhanot # , Jeremy Steen, Minahil Syed, Austin Mardon # Sharpen the Quill, Ontario, Canada

Vaccination is a powerful inducer of immunity against SARS-CoV-2 and its recent variants. However, it is important to expand the defensive repertoire against this virus as vaccination is not always efficacious or accessible to everyone. Protein therapeutics in the form of monoclonal antibodies have been used to neutralize the Spike protein, but their efficacy has been limited with rapidly evolving mutations. Cocktail antibodies have been used to combat antigenic escape through diversifying antigen recognition and the overall neutralization capacity. However, the production of cocktail antibodies can be costly and requires a high dosage to achieve the desired therapeutic effect. Alternatively, bispecific antibodies have been used, which contain two recognition specificities within the same molecule. This effectively reduces the cost of production and dosage required to achieve a target therapeutic effect. Bispecific antibodies were reported to bind SARS-CoV-2 antigen with nanomolar affinities. The neutralization potentials (IC50 values) within the same studies were generally more efficacious than their cocktail antibody counterparts. Some studies showed that bispecific antibodies could also confer additional neutralization effector functions, such as recruiting the complement system. Although the recognition of variants was diverse, to our knowledge, there is no data to suggest that bispecific antibodies have a broader recognition of variant strains than cocktail antibodies. Future studies should aim to explore the clinical benefits of bispecific antibodies for SARS-CoV-2 and the emerging variant strains to better understand its benefits in treatment.

Immunogenetic Association of 127 Human Leukocyte Antigen (HLA) Alleles with 30 Cancers in Continental Western European Countries

Apostolos P. Georgopoulos 1,2,3,4* , Lisa M. James 1,2,3 1 The HLA Research Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA 2 Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA 3 Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA 4 Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Human leukocyte antigen (HLA) genes have been associated with susceptibility and protection against a number of cancers. Here we used an immunogenetic epidemiological approach to evaluate the overall influence of 127 HLA Class I and II alleles on 30 types of cancer. We found a preponderance of protective alleles (negatively correlated with cancer prevalences), especially for HLA Class I. Of the 30 cancers investigated, 13 were associated with mostly protective HLA effects whereas only 2 were associated with mostly susceptibility HLA alleles. Taken together, these findings highlight the broad influence of HLA on cancer and the complexity of HLA-cancer associations.­­

Controlling the cGAS-STING Pathway: The Signature of ASFV Virulence

Raquel García-Belmonte, Daniel Pérez-Núñez, Yolanda Revilla * Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Microbes in Health and Welfare Department, c/ Nicolás Cabrera, 1, 28049 Madrid, Spain

Experimental Autoimmune Encephalomyelitis Animal Models Induced by Different Myelin Antigens Exhibit Differential Pharmacologic Responses to Anti-Inflammatory Drugs

Yuxi Yan 1# , Quan Zhao 1# , Ya Huang 1 , Janine Y. Yang 2 , Jie Zou 1 , Chunxia Ao 1 , Xiaojuan Chai 1 , Renhong Tang 1 and WenQing Yang 1* 1 State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, Jiangsu, China. 2 Massachusetts Eye and Ear, Harvard Medical School, USA

Background and objective

Experimental autoimmune encephalomyelitis (EAE) is the most commonly used model for studying autoimmune-mediated myelin degradation in multiple sclerosis (MS). Here, we evaluated the pharmacologic responses of several anti-inflammatory drugs with varying mechanisms of actions (MOAs) using EAE models induced by different MOG immunogens to reveal differential pharmacologic characteristics of the disease models and provide a general guidance in animal model selection for MS research.

The pharmacologic responses of anti-inflammatory drugs with different mechanisms of actions (MOAs) were evaluated using EAE models induced by either myelin oligodendrocyte glycoprotein p35-55 (MOG 35-55 )  or p1-128 (MOG 1-128 ). EAE animal models were developed in mice with C57BL/6 background. The animals were treated with different anti-MS medications, including 3 B cell-mediated agents and 2 T cell-mediated agents, respectively. Clinical symptoms were monitored and scored, and pharmacodynamic markers including cytokine secretion, inflammatory cell infiltration, and demyelination in spinal cord were analyzed.

In MOG 35-55 peptide-induced EAE model, T cell modulating agents Secukinumab and Fingolimod significantly alleviated clinical symptoms, while B cell-depleting agents, BTK inhibitors PRN2246 and Telitacicept, displayed minimal therapeutic effects or even exacerbated disease progression. In contrast, both T cell-modulating agents and B cell-depleting agents ameliorated disease severity in MOG 1-128 -induced EAE model. T cell and B cell infiltration in spinal cord increased with disease progression in MOG 1-128 -induced EAE model.

Conclusions

Our results demonstrated that induction of EAE by different myelin antigens resulted in differential pharmacologic responses to drugs with specific MOAs. The MOG 35-55 peptide-induced EAE model only responded to T cell-modulating drugs, whereas the MOG 1-128 protein-induced EAE model exhibited therapeutic sensitivity to both T cell- and B cell-modulating agents. These data suggest the MOG 35-55 peptide-induced EAE model is suitable for assessing T cell-modulating agents while MOG 1-128 protein-induced model can be employed to evaluate both T cell- and B cell-modulating agents.